1. Field
The present disclosure relates to a composition for promoting hair growth, or a therapeutic agent for hair loss.
2. Discussion of Related Technology
In addition to adipocytes, an adipose tissue is composed of microvessel endothelial cells, fibroblasts, myocytes, preadipocytes, etc. and is recently receiving attention since differentiation of mesenchymal stem cells into various tissues such as cartilages, bones, muscles and fats in a suitable environment has been reported. Recently, ASCs are applied to various fields for tissue regeneration and disease treatment, and particularly, since a large number of stem cells may be obtained from ASCs, compared to bone marrow or cord blood-derived mesenchymal stem cells, there is active clinical application of ASCs for skin, plastic surgery and beauty. Uncultured ASC extract fractions are clinically used in dermatology, plastic surgery, etc., and recently, a cellular therapeutic agent used for Crohn's disease has been approved.
ASCs are a type of mesenchymal stem cells that exhibit wound healing and antiaging effects on skin (Kim et al., J Dermatol Sci 53:96-102, 2009; Altman et al., Stem Cells 27:250-258, 2009). Recently, it was confirmed that the hair cycle of a mouse is shifted from telogen to an antigen phase due to ASCs pretreated with hypoxia or vitamin C (Won et al., J Dermatol Sci 57:134-137, 2010; Kim et al., Stem Cells Dev 23:1364-1376, 2014), which is caused by enhancing the hair regenerative potential of ASCs. As a growth factor expressed from ASCs and secreted, PDGF-A regulates the activity of hair follicular stem cells and induces the anagen of a hair cycle (Festa et al., Cell 146:761-771, 2011). In addition, injection of recombinant PDGF-A and B induces the anagen of murine hair follicles (Tomita et al., J Dermatol Sci 43:105-115, 2006).
PDGF is one of the growth factors that regulate cell growth and division (Andrae et al., Genes Dev 22:1276-1312, 2008; Kim et al., Development 130:4769-4784, 2003) and, as a mitogenic substance in an early developmental stage, affects the proliferation and migration of undifferentiated mesenchymal stem cells and some progenitor cells (Hannink et al., Biochim Biophys Acta 989:1-10, 1989; Heldin et al., EMBO J 11:4251-4259, 1992). In a later morphogenetic stage, PDGF signals are involved in tissue remodeling and cellular differentiation and play an important role in blood vessel formation. A PDGF signaling network includes four ligands such as PDGF-A, -B, -C and -D and two tyrosine kinase receptors such as PDGFR-α and PDGFR-β (Demoulin J B et al., Cytokine Growth Factor Rev 25:273-283, 2014; Levitzki A et al., Cytokine Growth Factor Rev 15:229-235, 2004). All PDGFs may form homodimers linked by a disulfide bond, and PDGF-A and -B may form heterodimers. When dimerized PDGFRs are activated, cytoplasmic domains are phosphorylated, and thus signal transduction is activated by the PI3K pathway or ROS generation (Blazevic T et al., J Biol Chem 288:35592-35603, 2013; Shimizu H et al., Am J Physiol Cell Physiol 297:C389-396, 2009; Lange S et al. Cardiovasc Res 81:159-168, 2009). PDGF-C and -D are recently found and bind with PDGFR-α and PDGFR-β, respectively (Bergsten E et al. Nat Cell Biol 3:512-516, 2001; LaRochelle W J et al., Nat Cell Biol 3:517-521, 2001). PDGF-D only forms homodimers and does not dimerize with the other three types of PDGFs. Also, PDGF-D is known to induce cell transformation and promote tumor growth (Li H et al., Oncogene 22:1501-1510, 2003).
In terms of the mitogenic effect of PDGFs on the mesenchymal stem cells, PDGF-B is known to regulate proliferation and invasion through the ERK and Akt signaling pathways (Sun X et al., Cell Signal 25:1279-1287, 2013), and PDGFR-α is known to be involved in formation of smooth muscle actin filaments in the mesenchymal stem cells (Ball S G et al., Int J Biochem Cell Biol 39:379-391, 2007). In addition, PDGFR inhibition mediated by an inhibitor regulates Oct4 and Nanog expression and changes cell morphology as well as the potency of the mesenchymal stem cells (Ball S G et al., Stem Cells 30:548-560, 2012). VEGF is involved in signal transduction in the mesenchymal stem cells through PDGFR (Ball S G et al., J Cell Biol 177:489-500, 2007), and PDGF induces proliferation and migration of ASCs through INK, and PDGF-B increases the proliferation and migration of ASCs through ROS generation and miR-210 increase (Kang et al., J Cell Biochem 95:1135-1145, 2005; Kim et al., Cell Death Dis 4:e588, 2013). PDGF secreted from ASCs induces the anagen of a hair cycle due to such a paracrine effect (Festa et al., Cell 146:761-771, 2011). ASCs present in an adipose tissue secrete PDGF-D and induce epithelial-mesenchymal transition (EMT) in breast cancer (Devarajan et al., Int J Cancer 131:1023-1031, 2012). Isoforms of PDGFs and their receptors serve as autocrines and paracrines in ASCs, but the mechanism for ASC regulation has not been fully identified.
The mitogenic effect of PDGF-B in ASCs has been known, and it is also known that PDGF-B is involved in the expression of growth factors such as PDGF-A, PDGF-B, VEGF, EGF, IGF and bFGF, and thus has a large influence on the proliferation and migration of ASCs (Kim et al., Cell Death Dis 4:e588, 2013; Kaewsuwan et al., Expert Opin Biol Ther 12:1575-1588, 2012). However, ASCs are exogenous since ASCs do not express PDGF-B. Also, it was confirmed that inhibition of PDGFR-β reduces the proliferation and migration of ASCs (Kim et al., Cell Death Dis 4:e588, 2013), and except PDGF-B, PDGF-A, -C and -D are expressed in ASCs (Devarajan et al., Int J Cancer 131:1023-1031, 2012). It has been shown that PDGF-D serves as a cell transformation factor and an angiogenetic growth factor through PDGFR-β in cancer cells (Li et al., Oncogene 22:1501-1510, 2003) and more effectively increases migration and invasion than PDGF-B (Najy et al., Mol Cancer Res 10:1087-1097, 2012). However, the function of PDGF-D in ASCs, particularly its effect on secretion of growth factors, has not been identified yet.